Augmentation Strategies in Treatment-Resistant Depression

October 30, 2006

The treatment of unipolar major depression presents a substantial challenge for the clinician. Major depression is a common disorder with a high propensity for relapse and recurrence.

The treatment of unipolar major depression presents a substantial challenge for the clinician. Major depression is a common disorder1 with a high propensity for relapse and recurrence.2 In addition, it is increasingly evident that antidepressant treatment offers moderate benefits and that sequential treatments are invariably required to obtain a satisfactory therapeutic effect.

Recent research findings confirm earlier observations that about 50% of patients with major depression respond to an adequate antidepressant trial, and far fewer, about one third, will achieve full remission.3,4 Moreover, if a patient fails to respond to 2 sequential antidepressant trials, remission rates are alarmingly low, approximately 10% to 15% with yet a third antidepressant.5 Remission is the goal of antidepressant therapy, yet it is estimated that first antidepressant trials (usually with an SSRI) fail in more than one half to two thirds of patients, requiring further therapeutic intervention. There are several options available for such patients; these are outlined in Table 1.

 
Switch to a second antidepressant
Augmentation of the SSRILithium Thyroid hormone Buspirone Antipsychotics Stimulants Anticonvulsants, etc
Combination of initial SSRI and a second antidepressant of another class
Switch to or add somatic therapiesElectroconvulsive treatment Rapid transcranial magnetic stimulation
Addition of specific psychotherapy

While there is limited clinical trial evidence for the efficacy of these options, few have undergone rigorous randomized, controlled trials. Furthermore, there are few data on the comparable efficacy of these various options. For example, a recent report from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial showed no significant difference in remission rates when either bupropion or buspirone was given to patients who failed to respond to or could not tolerate a trial of the SSRI citalopram.6

Nonetheless, a recent survey of a large Veterans Administration (VA) mental health population found that when an antidepressant produced an incomplete response, a second antidepressant or a second-generation antipsychotic were the most common drugs added to the regimen.7 Given the extremely limited data on the efficacy of both of those options, the findings are surprising and they underscore the need for a critical evaluation of the current clinical approach to treatment-resistant depression.

In the VA study, only one half of one percent of subjects received lithium augmentation despite the general acknowledgement that lithium has the strongest evidence to support its efficacy as an antidepressant augmentation agent.7 This article will focus narrowly on augmentation strategies and their utility as treatment options for refractory depression.

AUGMENTATION STRATEGIES

"Augmentation strategies" refers specifically to the addition of compounds that are not usually considered to have clinically substantial antidepressant properties when used alone. The early focus was on lithium and thyroid hormone but recently, other augmentation agents, such as buspirone, pindolol, and second-generation antipsychotics have received increasing attention. There is now a vast array of compounds that have been documented, mostly in case reports or small case series, as effective augmenting agents. Few have been subjected to rigorous clinical evaluation, so the focus here will be on those that have solid documentation or that are in common clinical use.

Lithium

The addition of lithium to a drug regimen is the best substantiated of the augmentation strategies. There have been numerous open-label studies that document the efficacy of lithium augmentation.8 Several double-blind controlled trials generally support the superiority of lithium to placebo in augmenting response to both tricyclic antidepressants and SSRIs (Table 2). These studies were limited by small sample sizes and short durations of treatment. However, a meta-analysis confirmed the superiority of lithium augmentation over placebo with a therapeutic advantage for treatment beyond 2 weeks with dosages of lithium carbonate in excess of 750 mg/d.8

    
StudyNAntidepressantDuration(days)Remarks
Heninger15TCA2Lithium greater efficacy than placebo
Kantor7TCA2Lithium greater efficacy than placebo
Zusky16TCA14Lithium greater efficacy than placebo
Schopf27TCA14Lithium greater efficacy than placebo
Browne17TCA2Lithium greater efficacy than placebo
Joffe33TCA14Lithium greater efficacy than placebo; equal to T3
Stein34TCA21Lithium greater efficacy than placebo (dosage 750 mg/d)
Katona61TCA and SSRI42Lithium greater efficacy than placebo
Baumann24SSRI7-14Lithium greater efficacy than placebo
Fava101SSRI28Lithium equal to desipramine equal to fluoxetine dose increase (no placebo)
Nierenberg35TCA42Lithium greater efficacy than placebo


Thyroid hormone

Thyroid hormone, particularly triiodothyronine (T3) has also received considerable attention as an augmentation strategy (Table 3). Although most studies have been open-label and involve tricyclics, a meta-analysis confirmed the superiority of T3 over placebo20 and found evidence of the clinical utility of T3 for both tricyclic and SSRI augmentation.21-33 In the only study to directly compare T3 and lithium augmentation, the 2 agents were found to be comparable in efficacy, and both were superior to placebo.14

      
StudyNAntidepressantDesignDuration (days)Remarks 
Earle25TCAOpen-label2114/25 responded 
Banki52TCAOpen-label1039/52 responded 
Banki33TCAControlled7T 
Ogura44TCAOpen-label2829/44 responded 
Tsutsui11TCAOpen-label1410/11 responded 
Goodwin12TCADouble-blind288/12 responded 
Schwarcz8TCAOpen-label284/8 responded 
Gitlin16TCADouble-blind10No difference T 
Thase20TCAOpen-label285/20 responded 
Joffe38TCADouble-blind21T 
Joffe1451TCADouble-blind14T 
Agid25TCAOpen-label2111/25 responded 
Iosifescu20SSRIOpen-label147/20 responded 
Abraham12SSRIOpen-label285/12 responded 


Like the lithium studies, the T3 studies have several limitations. In particular, the duration of treatment--as short as 6 to 14 days for several T3 studies and 2 days in some lithium studies--appears to be a major shortcoming. However, given the documented response rates of more than 50% for each strategy and the positive findings of clinical efficacy,8,20 one could argue that these findings are highly encouraging. Results might be even more impressive in a trial of adequate duration--about 4 to 6 weeks.

Most studies have focused on the use of T3 as an augmentation strategy; the clinical utility of thyroxine (T4) remains unresolved.34 To reduce the risk of thyrotoxic symptoms, T3 should be administered in modest dosages of about 25 µg/d and certainly at dosages well below those required for replacement therapy. No dose-response relationship has been demonstrated for the antidepressant augmenting effect of T3, and at lower doses adverse effects are minimal.

Buspirone

Augmentation with buspirone produced encouraging results in open studies of serotonergic antidepressants, but 2 placebo-controlled trials failed to separate buspirone from placebo.35,36 In these 2 studies, buspirone was efficacious in more than half of the subjects, but placebo was comparably efficacious. The findings are difficult to interpret: subjects who were treatment-resistant would not be expected to have high placebo response rates in an augmentation study.35,36 The recent observation that buspirone and bupropion produced comparable clinical benefits following citalopram failure6 should rekindle interest in buspirone as an augmentation strategy given its favorable side-effect profile (although bupropion performed better on some secondary outcome measures and was better tolerated).

Pindolol

Pindolol, a serotonin 5HT1A receptor antagonist, initially generated much optimism regarding its use as an augmentation agent, but in controlled trials, it produced disappointing results. A recent meta-analysis concluded that pindolol is not a clinically effective augmentation strategy, although this may be explained by the inadequate doses employed in the included studies; at higher doses, the clinical utility of pindolol remains uncertain.37 A small placebo-controlled trial found that a single daily dose of 7.5 mg of pindolol was effective for paroxetine-resistant depression.38

Atypical antipsychotics

In the VA study mentioned above, the atypical antipsychotics were the second most common augmentation strategy used.7 Compounds that have been shown to augment antidepressant response in open-label studies include risperidone, aripiprazole, olanzapine, and ziprasidone.39-41 However, the limited number of controlled trials of antipsychotic antidepressant augmentation have produced inconclusive, largely negative data on their clinical efficacy.42 Since the use of this class of drug for this indication may be broadening, adequately designed and powered studies are required to evaluate their effectiveness for treatment-refractory depression.

Other augmentation strategies

Other common augmentation strategies include psychostimulants, for which there is very limited empiric support, and anticonvulsants. The latter are commonly used in bipolar disorder, but their role in unipolar treatment-resistant depression has been studied less and is, therefore, less understood. In particular, lamotrigine would be of interest as an antidepressant augmentation agent, given its antidepressant efficacy in bipolar illness. However, to date, the results of studies on the antidepressant augmenting effect of lamotrigine are mixed; there has been 1 small study with positive results43 and 2 studies with negative results.44,45

SUMMARY AND CONCLUSIONS

Of the various augmentation strategies, lithium and T3 show considerable promise as effective augmentation agents; the effectiveness of busprirone requires further consideration given the results of the STAR*D trial. These compounds, however, seem to have limited use and one could reasonably conclude that they have fallen out of favor with clinicians as useful treatments for depression.7

The problems with lithium are obvious: its high side-effect burden, the need for continual monitoring, and the potential long-term effects on organs, such as the thyroid and kidney. In light of its well-established efficacy, however, and the limited successes of other antidepressant options,4-6 it still may be underused.7

The perception of T3 is that it is not as effective as lithium or that it will not work with SSRIs. Although the literature is limited, there is some evidence of the comparable efficacy of T3 and lithium, and 3 studies confirm the efficacy of T3 when it is added to an SSRI.31-33

Notwithstanding the need for proof of the clinical efficacy of T3 and bu-spirone, on the basis of the evidence to date, these compounds appear safe and effective, with limited need for patient monitoring, and they have no documented long-term adverse effects. Although most augmentation studies have been of short duration, it is possible that an augmentation agent, once effective, should be maintained for the period of antidepressant therapy and even during maintenance treatment which may extend over months or years. T3 and buspirone would be ideal for such long-term use, although there would be greater concern about long-term lithium treatment. The second-generation antipsychotics appear to be increasingly popular as augmentation agents; however, the risk of the metabolic syndrome, the adverse cardiac sequelae, and the need for regular monitoring should raise concern over their potential for long-term use.

Augmentation strategies represent a viable alternative for patients with major depressive illness who do not respond to initial antidepressant therapy. The early augmentation agents have been largely overlooked despite their often better-established efficacy and, as is certainly the case with T3, a favorable side-effect profile. These compounds need a careful reappraisal as viable treatment options because refractory depression is a disorder with a high nonresponse rate and a high risk of recurrence and chronicity.

Lithium also needs a favorable reappraisal given its well-documented efficacy and because commonly used second-generation antipsychotics appear to have little, if any, advantage over lithium in terms of monitoring and short- and long-term adverse sequelae. Ultimately, given the limited efficacy of the various options for sequential treatment,4-6 no viable treatment can be ignored. It may not be so much a factor of whether one agent is better than another, but rather that all should be considered and used appropriately to effect the best treatment result.

Dr Joffe is a professor in the department of psychiatry at the New Jersey Medical School in Newark. He reports no conflicts of interest concerning the subject matter of this article.

References:

REFERENCES:


1.

Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R).

JAMA.

2003;289:3095-3105.

2.

Keller MB, Klerman GL, Lavori PW, et al. Long term outcome of episodes of major depression: clinical and public health significance.

JAMA.

1984;252:788-792.

3.

Keller MB, Lavori PW, Mueller TI, et al. Time to recovery, chronicity and levels of psychopathology in major depression: a 5 year prospective follow-up of 431 subjects.

Arch Gen Psychiatry.

1992;49:809-816.

4.

Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement based care in STAR*D: implications for clinical practice.

Am J Psychiatry.

2006;163:28-40.

5.

Fava M, Rush AJ, Wisniewski SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report.

Am J Psychiatry.

2006;163: 1161-1172.

6.

Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after failure of SSRIs for depression.

N Engl J Med.

2006;354:1243-1252.

7.

Valenstein M, McCarthy JE, Austin KL, et al. What happened to lithium? Antidepressant augmentation in clinical settings.

Am J Psychiatry.

2006;163: 1219-1225.

8.

Bauer M, Dopfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies.

J Clin Psychopharmacol.

1999;19: 427-434.

9.

Heninger GR, Charney DS, Sternberg DE. Lithium carbonate augmentation of antidepressant treatment: an effective prescription for treatment-refractory depression.

Arch Gen Psychiatry.

1983;40:1335-1342.

10.

Kantor D, McNevin S, Leichner P, et al. The benefit of lithium carbonate adjunct in refractory depression: fact or fiction?

Can J Psychiatry.

1986;33:416-418.

11.

Zusky PM, Biederman J, Rosenbaum JF, et al. Adjunct low dose lithium carbonate in treatment-resistant depression: a placebo-controlled study.

J Clin Psychopharmacol

. 1988;8:120-124.

12.

Schopf J, Baumann P, Lemarchand T, Roy M. Treatment of endogenous depressions resistant to tricyclic antidepressants or related drugs by lithium addition; results of a placebo-controlled double-blind study.

Pharmacopsychiatry.

1989;22:183-187.

13.

Browne M, Lapierre YD, Hrdina PD, Horn E. Lithium as an adjunct in the treatment of major depression.

Int Clin Psychopharmacol

. 1990;5:108-110.

14.

Joffe RT, Singer W, Levitt AJ, MacDonald C. A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression.

Arch Gen Psychiatry.

1993;50: 387-393.

15.

Stein G, Bernadt M. Lithium augmentation therapy in tricyclic-resistant depression: a controlled trial using lithium in low and normal doses.

Br J Psychiatry.

1993; 162:634-640.

16.

Katona CL, Abou-Saleh MT, Harrison DA, et al. Placebo-controlled trial of lithium augmentation of fluoxetine and lofepramine.

Br J Psychiatry.

1995;166: 80-86.

17.

Baumann P, Nil R, Souche A, et al. A double-blind, placebo-controlled study of citalopram with and without lithium in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic investigation.

J Clin Psychopharmacol.

1996; 16:307-314.

18.

Fava M, Rosenbaum JF, McGrath PJ, et al. Lithium and tricyclic augmentation of fluoxetine treatment in resistant major depression: a double-blind controlled study.

Am J Psychiatry.

1994;151:1372-1374.

19.

Nierenberg AA, Papakostas GI, Peterson T, et al. Lithium augmentation of nortriptyline for subjects resistant to multiple antidepressants.

J Clin Psychopharmacol.

2003;23:92-95.

20.

Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment of refractory depression: a meta-analysis.

Arch Gen Psychiatry.

1999; 53:842-848.

21.

Earle BV. Thyroid hormone and tricyclic antidepressants in resistant depressions.

Am J Psychiatry.

1970; 126:1667-1669.

22.

Banki CM. The use of triiodothyronine in the treatment of depression [in Hungarian].

Orv Hetil.

1975;116: 2543-2546.

23.

Banki CM. Cerebrospinal fluid amine metabolites after combined amitriptyline: triiodothyronine treatment of depressed women.

Eur J Clin Pharmacol.

1977; 11:311-315.

24.

Ogura C, Okuma T, Uchida Y, et al. Combined thyroid (triiodothyronine)-tricyclic antidepressant treatment in depressed states.

Folia Psychiatr Neurol Jpn.

1974;28: 179-186.

25.

Tsutsui S, Yamazaki Y, Nanba T, Tsushima M. Combined therapy of T

3

, and antidepressants in depression.

J Int Med Res.

1979;7:138-146.

26.

Goodwin FK, Prange AJ Jr, Post RM, et al. Potentiation of antidepressant effects by L-triiodothyronine in tricyclic nonresponders.

Am J Psychiatry.

1982;139:34-38.

27.

Schwarcz G, Halaris A, Baxter L, et al. Normal thyroid function in desipramine nonresponders compared to responders by the addition of L-triiodothyronine.

Am J Psychiatry.

1984;141:1614-1616.

28.

Gitlin MJ, Winer H, Fairbanks L, et al. Failure of T

3

to potentiate tricyclic antidepressant response.

J Affect Disord.

1987;13:267-272.

29.

Thase ME, Kupfer DJ, Jarrett DB. Treatment of imipramine-resistant recurrent depression: I. An open clinical trial of adjunctive L-triiodothyronine.

J Clin Psychiatry.

1989;50:385-388.

30.

Joffe RT, Singer W. A comparison of triiodothyronine and thyroxine in the potentiation of tricyclic antidepressants.

Psychiatry Res.

1990;32:241-252.

31.

Agid O, Lerer B. Algorithm-based treatment of major depression in an outpatient clinic: clinical correlates of response to a specific serotonin reuptake inhibitor and to triiodothyronine augmentation.

Int J Neuropsychopharmacol.

2003;6:41-49.

32.

Iosifescu DV, Nierenberg AA, Mischoulon D, et al. An open study of triiodothyronine augmentation of selective serotonin reuptake inhibitors in treatment-resistant major depressive disorder.

J Clin Psychiatry.

2005;66:1038-1042.

33.

Abraham G, Milev R, Stuart Lawson J. T

3

augmentation of SSRI resistant depression.

J Affect Dis.

2006;91: 211-215.

34.

Baumgartner A. Thyroxine and the treatment of affective disorders: an overview of the results of basic and clinical research.

Int J Neuropsychopharmacol.

2000;3: 149-165.

35.

Landen M, Bjorling G, Agren H, Fahlen T. A randomized, double-blind, placebo-controlled trial of buspi- rone in combination with an SSRI in patients with treatment-refractory depression.

J Clin Psychiatry.

1998;59:664-668.

36.

Appelberg BG, Syvalahti EK, Koskinen TE, et al. Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind placebo wash-in study.

J Clin Psychiatry.

2001;62:448-452.

37.

Segrave R, Nathan PJ. Pindolol augmentation of selective serotonin reuptake inhibitors: accounting for the variability of results of placebo-controlled double-blind studies in patients with major depression.

Hum Psychopharmacol.

2005;20:163-174.

38.

Sokolski KN, Conney JC, Brown BJ, DeMet EM. Once daily high-dose pindolol for SSRI-refractory depression.

Psychiatry Res.

2004;125:81-86.

39.

Nemeroff CB. Use of atypical antipsychotics in refractory depression and anxiety.

J Clin Psychiatry.

2005;66 (suppl 8):13-21.

40.

Rapaport MH, Gharabaw GM, Canuso CM, et al. Effects of risperidone augmentation in patients with treatment-resistant depression: results of open-label treatment followed by double-blind continuation.

Neuropsychopharmacologyl.

2006 Jun 7; [E pub ahead of print].

41.

Simon JS, Nemeroff CB. Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder.

J Clin Psychiatry.

2005;66:1216-1220.

42.

Shelton RC, Williamson DJ, Corya SA, et al. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance.

J Clin Psychiatry.

2005;66:1289-1297.

43.

Gabriel A. Lamotrigine adjunctive treatment in resistant unipolar depression: An open, descriptive study.

Depress Anxiety.

2006 Jul 14; [Epub ahead of print].

44.

Normann, C, Hummel, B, Scharer, Lo, et al. Lamotrigine as adjunct to paroxetine in acute depression: a placebo-controlled, double-blind study.

J Clin Psychiatry.

2002;63:337-344.

45.

Barbosa, L, Berk, M, Vorster, M. A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes.

J Clin Psychiatry.

2003;64:403-407.